16alpha-chloro-1, 4-pregnadienes



United States Patent 3,137,712 la-CHLOBO-IA-PREGNADHENES Robert D.Birkenmeyer, Fred Kagan, and Barney J.

Magerlein, Kaiamazoo, and William P. Schneider, Kalamazoo Township,Kalamazoo County, Mich, assignors to The Upjohn Company, Kalamazoo,Mich., a corporation of Delaware No Drawing. Filed Oct. 13, 1961, Ser.No. 144,830

9 Claims. (Cl. 260397.45)

This invention relates to novel l6a-chloro steroids and novel steroidintermediates and methods used in the preparation thereof.

The novel l6a-chloro-llfi-hydroxy steroid compounds of this inventionare represented by the formula:

wherein R is selected from the group consisting of hydrogen, hydroxyl,OAcyl, and OPO H the term Acyl representing the acyl radical of anorganic carboxylic acid, particularly a hydrocarbon carboxylic acidcontaining from 1 to 12 carbon atoms, inclusive; X is selected from thegroup consisting of hydrogen and fluorine, and Y is selected from thegroup consisting of hydrogen, methyl and fluorine. Also of interest arethe 17-esters, particularly the l7-acetates, of those compounds ofFormula I wherein R is hydrogen.

The compounds of Formula I possess useful therapeutic properties, namelyanti-inflammatory and glucocorticoid activity. Thus, for example,9a-fluoro-16a-chloro-11 3, 17a,2l trihydroXy-1,4-pregnadiene-3,20-dione2l-acetate (9u-fluoro-l6u-chloro-prednisolone 21-acetate) has been foundto exhibit approximately 360 times the glucocorticoid activity ofhydrocortisone, approximately 313 times the anti-inflammatory activityof hydrocortisone, and in addition has a favorable eflect on salt andwater balance.

The high activity of 9a-flouoro-l6a-chloroprednisolone Zl-acetate is themore surprising as other 16-substituted compounds have considerablylower activity (cf. Table I):

The compounds of Formula I are useful in the treatment of inflammatoryconditions of mammals and birds and are particularly useful in thetreatment of inflammatory conditions of the skin, eyes and ears ofhumans and of valuable domestic animals, as well as contact dermatitisand other allergic reactions.

3,137,712 Patented June 16, 1964 ice Administration of the novelsteroids of Formula I can be in conventional dosage forms, such aspills, tablets,

1 1B, l7u,2i-trihydroxy-16a-chloro-1,4-pregnadiene-3,20-

dione,

9a-fluoro-11,8,17u,21-trihydroxy-16u-chloro-1,4-pregnadiene-3 ,ZO-dione,

6a-fluoro-1 1p,17,21-trihydroxy-16a-ch1oro-1,4-pregnadiene-3,20-dione,

6a-methyl-1 1,3,17a,21-trihydroxy-l6a-chloro-L4-pregnadiene-3,20-dione,

6u-methyl-9a-fluoro-1 1 3,17a,2l-trihydroxy-16a-chloro-l,4-pregnadiene-3,20-dione, and the 32 lacylates thereof;

1 1,6, l7a-dihydroxy-16a-ch1oro-l,4-pregnadiene-3,20-

dione,

6a-fluoro-1 1B,17a-dihydroxy-16a-chloro-1,4-pregnadiene- 3 ,20-dione,

60,90t-dlfillOIO-l 1,8,17a-dihydroxy-16a-chloro-1,4-pregnadiene-3,20-dione,

6a-methyl-l 1B,17a-dihydr0xy-16u-chloro-l,4-pregnadiene-3,20-dione,

6a-methyl-9 a-fluoro-l 6a-chloro-l 15,17a-dihydroxy-L4-pregnadiene-3,20-dione, and the 17-acylates thereof;

1 1,8, 1704,21-trihydr0xy-16a-chloro-1,4-pregnadiene-3 ,20-

dione 2 l-phosphate,

9a-fiuoro-1 1B,17a,21-trihydroxy-16a-chloro-1,4-pregnadiene-3,20-dione21-phosphate,

6ol-flll01O-1 1 8,l7a,2l-trihydroxy-l6u-chloro-1,4-pregnadiene-3,20-dione 21-phosphate,

6 zx-methyl-l 1B,17a,21-trihydroxy-16a-chloro-1,4-pregnadiene-3,20-dione21-phosphate,

6 a-methyl-9 a-flLlOI'O-l 1,6, 1 7a,2 l-trihydroxy-16a-chloro-1,

4-pregnadiene-3,20-dione 2l-phosphate,

are prepared according to the following reaction scheme:

om l\ o OHzOAc i: no 1-1 1| nofl fi H-fit T01 Ha III To cnzoAc on HnofA-cr i 0 From onion CHQOAc 3:0 :0

CHQOAG XII wherein R is selected from the group consisting of hydrogenand Ac, wherein Ac is an acyl radical of an organic carboxylic acid,particularly a hydrocarbon carboxylic acid containing from 1 to 12carbon atoms, inclusive; X is selected from the group consisting ofhydrogen and fluorine and Y is selected from the group consisting ofhydrogen, methyl and fluorine.

The process diagramrned above comprises the following steps: treating aselected 11fi-hydroxy-20,2l-oxido-l,4, 16-pregnatrien-3 one (II) withhydrogen chloride and then with an acid anhydride to give thecorresponding 1 1Bhydroxy-16a-chloro-21-acy1oxy-1,4,17(20)-pregnatrien-3-one (III); or,alternatively, treating a selected 1lB-hydroxy-20,21-oxido-4,16-pregnadien-3-one (IIa) with hydrogenchloride and then with an acid anhydride to obtain the correspondingIlfi-hydroxy-l 6a-chloro-21-acyloxy 4,17 (Z0) --pregnadien-3-one (IIIa)which is converted with selenium dioxide to the corresponding A steroidcompound of Formula III; treating compound III with osmium tetroxide andan organic peroxide or osmium tetroxide and an aryliodoso acetate toproduce the corresponding 1 1,8,Hall-trihydroxy-la-chloro-lA-pregnadiene-3,20dione 21-acylate (IV);dehydrating compound IV with a N-haloacylamide and sulfur dioxide togive the corresponding :,21 dihydroxyl6a-chloro-1,4,9(11)-pregnatriene-3,20-dione 21-acy1ate (V); treating compound V withN-haloacylamide, such as N-bromoacet- ,amiide, N-chioroacetamide orN-brornosuccinimide to give the corresponding1lfi,170,2rl-trihydroxy-9a-ialo- 16a-chloro-1,4-pregnadiene-3,ZO-dione2l-acylate (VI); treating compound VI with a mild base such as potassiumor sodium acetate to give the corresponding 9,8,11,8-oxid0- 170;,21dihydroxy-'16a-chloro-1,4-pregnadiene-3,20-dione 21-acylate (VII);treating compound VII with hydrogen fluoride to give the corresponding9a-fluoro-11p,17a,21- trihydroxy 1611- chloro-1,4-pregnadiene-3,ZO-dione 21- acylate (VIII).

. Inasmuch as the above-cited compounds are 2l-esters, they can besaponified with bases such as sodium carbonate, potassium carbonate, orbicarbonates of alkali metals, preferably under exclusion of air in anitrogen atmosphere, to give the corresponding free alcohols such as,for example, from compound IV the corresponding 11/3,170c,21 trihydroxy16oa-chloro-1,4-pregnadiene-3, ZO-dione (IVA) or from compound VIII,9a-fluO10-11B, 17a,21 trihydroxy 16cc chloro-1,4pregnadiene-3,20- dione(VIIIA).

21-desoxy compounds are obtained by treating an alcohol of Formula IXwherein X can be hydrogen or fluorine and Y can by hydrogen, methyl orfluorine with an organic sulfonyl chloride such as methane-, ethane-, orpropanesulfonyl chloride, p-toluenesulfonyl chloride or benzenesulfonylchloride, and so on to give the corresponding 21-ester (X); treatingcompound X with an alkali iodide in acetone results in the corresponding115, 17a dihydroxy-l6u-chloro-21-iodo-1,4-pregnadiene-3,20- dione (XI);treating compound XI with a reducing agent such as alkali thiosulfates,sodium sulfite, sodium bisulfite, other alkali thiosulfates and sulfitesor zinc and acetic acid gives the corresponding 11,8,17a-dihydroxy-16a-ChlOIO-l ,4-pregnadiene-3,ZO-dione (XII) The introduction of the16ct-chloro group into a steroid can also be made by the followingalternative step: treating with thionyl chloride or phosphorustrichloride an 115,16,21 trihydroxy-1,4,17(20)-pregnatriene-21-acylate(XIII), as shown below:

The starting materials of these syntheses are prepared by the methoddescribed by Magerlein, Birkenmeyer and Kagan in J. Am. Chem. Soc., 82,1252 (1960). Further details for the synthesis of other startingmaterials are given under preparations.

In carrying out the process of the present invention, the selected11B-hydroxy-20,21-oxido-1,4,16-pregnatrien- 3-one, dissolved in asuitable organic solvent such as methylene chloride, ethylene chloride,chloroform, and the like is reacted with gaseous hydrogen chloride. Thetemperature of the reaction is preferably between and 15 buttemperatures from 80 to +25 C. are operative. Depending on thetemperature and solvent chosen, the time of reaction may last betweenhalf an hour and 24 hours or longer. In the preferred embodiment of thisinvention the steroid, dissolved in the solvent such as methylenechloride, ethylene chloride, and the like is added to a cooled solutionof hydrogen chloride in a similar solvent plus some tetrahydrofuran. Themixture is then allowed to stand from /2 to 24 hours at temperaturesbetween 0 and 15 C.

The thus-obtained reaction mixture is distilled under vacuum to removeexcess hydrogen chloride and solvents and the thus-obtained residuewithout further purification is redissolved in pyridine. To the pyridinesolution an acid anhydride is added such as acetic anhydride, propionicanhydride, or benzoic anhydride and the like and the mixture allowed tostand at room temperature or any temperature between 0 and 40 forseveral hours or more; preferably over night.

After this period, the mixture is poured into water and extracted withchloroform, methylene chloride or the like to recover the thus-obtained11,8-hydroxy-16a-chloro- 21-acyloxy-1,4,17(20)-pregnatrien-3 -one21-acylate.

The thus-obtained product can be purified by any conventional methodsuch as chromatography, recrystallization from organic solvents such asether, methanol, ethanol, methylene chloride, ethylene chloride and thelike to give the pure, desired 11,8,21-dihydroxy-16a-chloro-1,4,17(20)-pregnatrien-3-one 21-acylate (III).

The thus-obtained compound III is submitted to an oxidativehydroxylation reaction with osmium tetroxide in the presence of anoxygenating agent such as hydrogen peroxide, organic peracid, alkylperoxide, amine oxide peroxide, organic polyvalent iodooxide, such asiodoxybenzene, aryliodoso compounds, for example iodosobenzene,phenyliodoso acetate and the like. The reaction is best carried out in asolvent such as tertiary butyl alcohol at temperatures between 0 and 45C. and as described in great detail in US. Patents 2,769,825, 2,769,823,and 2,875,217. The thus-obtained11B,17a,21-trihydroxy-16achloro-1,4-pregnadiene-3,20-dione 21-acetate(IV), is purified by standard methods such as solvent extraction,chromatography, and recrystallization or a combination thereof usingsolvents such as methylene chloride, acetone, methanol, Skellysolve Bhexane, and the like.

The thus-obtained ester of configuration 1V can be saponified by amethod well known in the art such as by the use of sodium or potassiumhydroxide, carbonate or bicarbonate, calcium hydroxide, barium hydroxideand the like in alcoholic solutions, preferably under exclusion of air,in a nitrogen atmosphere, at low temperatures between 0 and 30". In thismanner the free alcohol, 11B,17a,21 trihydroxy 16cc chloro 1,4pregnadiene- 3,20-dione, is obtained which if desired can bereesterified with acid anhydrides, acid chlorides, and acid bromides, ororganic acids in the presence of a catalyst such as toluenesulfonic acidin conventional manner.

The dehydration of compound IV can be carried out by any methods knownin the arts, for example by dehydrating agents such as phosphorusoxychloride, hydrochloric acid or sulfuric acid or acetic acid. In thepreferred method the dehydration is eiiected by reacting the 1113-hydroxy compound with an acid N-haloamide or N-haloimide in a base andtreating the thus-produced intermediate with dry sulfur dioxide in anorganic base. As reagents for producing the intermediate noted above,the acid N-haloamides or N-haloimides are used wherein the halogen hasan atomic number from 17 to 53, inclusive, preferably chlorine orbromine. Examples of such reagents are N chloroacetamide,N-bromoacetamide, N-chlorosuccinimide, N-bromosuccinimide,N-iodosuccinimide, 3-bromo-5,5-dimethylhydantoin and1,3-dibromo-5,5-dimethylhydantoin. Ordinarily an amount in excess of amolar equivalent, calculated on the starting llfi-hydroxy steroid, isemployed. As solvents, pyridines such as pyridine, alkyl-pyridine,picoline, lutidine, collidine, parvuline or the like or lower fatty acidamides such as formamide and dimethylformamide are used. The dehydrationreaction is generally conducted under anhydrous conditions, preferablyat a concentration of less than 0.1 molar equivalent of water calculatedper mole of steroid. Large proportions of water decrease the yield.Ordinarily, room temperature (20 to 30 C.) is preferred and a reactionperiod between five minutes to three hours is usually employed. Thereaction mixture, preferably at a temperature of between 20 and 30 C.,is then treated with anhydrous sulfur dioxide in the presence of anorganic base such as the before-mentioned pyridine or acid amides. Thisreaction may be carried out at temperatures between -40 and +70 C. Thereaction mixture, after saturation with sulfur dioxide, is poured intowater, the crude product extracted, and if desired purified bychromatography or recrystallization to give pure17a,21-dihydroxy-16a-chloro-1,4,9(11)-pregnatriene-3,20-dione 21-acylate(V).

The thus-obtained compound V is treated with hypohalous acid such ashypochlorous or hypobromous acid. The hypohalous acid is usuallyprepared by reacting an acid N-haloamide or an N-haloimide with an acidto produce the hypohalous acid in situ. In the preferred embodiment ofthe invention, compound V is dissolved in an organic solvent such asmethylene chloride, tertiary butyl alcohol, dioxane, tertiary amylalcohol, ethylene dichloride, or the like and reacted at roomtemperature with the hypobromous or hypochlorous acid releasing agent inthe presence of an acid. Such hypohalous acid releasing agents includethe N-bromoacetamide, N-chloroacetamide, N-bromosuccinimide,N-iodosuccinirnide, and the like in the presence of water and an acidsuch as perchloric acid, dilute sulfuric acid, or the like. The reactioncan be carried out at temperatures between 15 and 35 C. however, loweror higher tempertaures are operative for the process. The reactionperiod is rather short and may vary between 4 to minutes to 1 hour. Atthe end of the reaction time excess of hypohalous acid is destroyed bythe addition of sodium sulfite or other sulfites or hydrosulfites. Thematerials thus obtained, 90ciodoor 9vt-chloroor91x-bromo-16u-chloro-1lfi,17a,2ltrihydroxy-l,4-pregnadiene-3,20-dione21-acylate (VI) can be recovered by concentrating the mixture underreduced pressure, diluting with water and collecting the solidprecipitate. Product VI can also be recovered by extraction from thereaction mixture by conventional extractions, with water-immisciblesolvents, such as ether, Skellysolve B hexanes, methylene chloride, andthe like. If desired, the product can be purified by chromatography andrecrystallization in known manner, but for the purpose of the subsequentreaction, the crude material is usually employed.

Cyclization of compound VI is obtained by treating this compound at anelevated temperature With a mild base. Bases useful for this purpose areanhydrous potassium acetate, sodium or potassium bicarbonate, sodiumacetate, or the like with potassium acetate preferred. The reaction iscarried out in a solvent such as methanol, ethanol, acetone, tertiarybutyl alcohol, or the like. The reaction time is usually between /2 hourand 24 hours. The product, 9fl,1l5-oxido-16a-chloro-l7a,21-dihydroxy-1,4-pregnadiene-3,20-dione 21-acylate (VII), is recoveredby con? ventional means such as removing the solvent by evaporating thereaction mixtures, preferably in vacuo, and extracting the residue witha water-immiscible organic solvent such as methylene chloride, ethylenedichloride, ether, and the like. The extracts are concentrated and ifdesired may be purified by chromatography or be reduced to dryness andthe crude material, thus obtained, used for the subsequent steps.

The thus-obtained compound VII,9,8,l1fi1-oxido-16achloro-17a,21-dihdroxy-1,4-pregnadiene-3,20 dione 21-acylate, is thereupon reacted with hydrogen fluoride. The reaction maybe performed with aqueous 48% hydrogen fluoride or preferably withanhydrous hydrogen fluoride, cooled to about -60 to 80 C. As solvent,tetrahydrofuran and methylene dichloride are preferred. The mixtures arepreferably stirred for 1 to 48 hours at low temperatures such as 70 to+l5. Thereafter, the reaction mixture is poured into a solution of analkali carbonate such as sodium carbonate, potassium carbonate, orbicarbonate thereof to be neutralized. The product is obtained byextraction with water-immiscible organic solvents such as methylenechloride, ether, benzene, and the like. The extract may be purified bychromatography or the product may be obtained by evaporating theextracts, and recrystallizing the thus-obtained solid residue. Theproduct thus obtained is 9a-fiuorollB,17a,21-trihydroxy-l6u-chloro-1,4-pregnadiene-3,20-dione 21 acylate(VIII).

From compound VIII the free alcohol, 9ot-fiuoro-1lfi,l7ot,21-trihydroxy-l6a-chloro-l,4-pregnadiene-3,20 dione (VIIIA), can beobtained by submitting the ester (VIII) to saponification as describedwith compound IV. The free alcohol VIIIA can be reesterified in knownmanner to give other esters having from 1 to 12 carbon atoms in theester group.

In order to prepare the 21-desoxy compounds, it is necessary to use asstarting material the free steroid alcohols which are genericallyindicated in the earlier shown flow sheet as compound IX. The compoundof structure IX is treated with a halideof an organic sulfonic acid,such as the chloride or bromide of methanesulfonic acid, ethanesulfonicacid, propanesulfonic acid, oc-Ol finaphthalenesulfonic acid,p-toluenesulfonic acid, benzenesulfonic acid, or the like, withmethanesulfonic acid halides, especially methanesulfonyl chloridepreferred. In

the preferred embodiment of this invention compound IX,

is reacted with the alkylor arylsulfonyl halide, in solution in asolvent, such as for example, pyridine, benzene, toluene, or the like,at a temperature between 10 and +30 C., providing that at the lowertemperature the reaction mixture has not solidified. The use of pyridineas solvent and a temperature between -10 and +10 C. is preferred. Thetime of reaction is between 30 minutes and 24 hours, after which theproduct, a 16zx-Ch1010-11fl,17a,21-trihydroxy-l,4-pregnadiene-3,20-dione 21-organic sulfonate (X),is recovered from the reaction mixture in conventional manner, forexample, by evaporating the solvent until a dry residue is obtained,precipitating the product by addition of water, or by extracting thematerial from an aqueous solution. For the extraction, solvents such asmethylene chloride, chloroform, carbon tetrachloride, benzene, ether,toluene, or the like may be used. Removing the extraction solvent bydistillation leaves the crude 11B,17a,-21-trihydroxy 160achloro-1,4-pregnadiene-3,20-dione 21-organic sulfonate (X).

Treating compound X with sodium or potassium iodide in acetone solutiongives the corresponding llfi,17a-dihydlOXY-16ocChIOI0*21l0d0-1,4pregnadiene 3,20 dione (XI). The reaction is usually carried out with anexcess of sodium or potassium iodide, three to twenty moles of thealkali metal iodide per mole of steroid. The temperature is usually therefluxing temperature of the acetone solution and the time for thereaction is from 3 to 4 minutes to a half hour. Evaporating the solventsleaves the desired 1lB,l'7u-dihydroxy-16a-chloro-21-iodo-L4-pregnadiene-3,20-dione (XI).

Compound XI is thereupon reacted with a reducing agent such as sodium orpotassium thiosulfate, sodium bisulfite, or the like. In the preferredembodiment of the invention, compound X1 is slurried in acetic acid, andthereto is added the aqueous solution of sodium or potassiumthiosulfate, bisulfite, or the like. The mixture is then stirred atroom. temperature for a period of 10 minutes to 2 hours and the productis isolated from the reaction mixture by conventional methods such asfiltration or extraction with a water-immiscible organic solvent such asether, benzene, methylene chloride, ethylene chloride, chloroform,hexane, heptane, or the like, and evaporation of the extracts.Purification of the thus obtained llfi, 17a-dihydroxy16tz-chloro-1,4-pregnadiene-3,2O dione (XII) is carried out byconventional means such as recrystallization or chromatography.

The thus-obtained 11,8,l7a-dihydroxy-l6a-chloro-l,4-pregnadiene-3,20-dione (XII) can be selectively esterified with an acidanhydride in acetic acid solution and in the presence of an acidcatalyst such as para-toluenesulfonic acid. The esterification iscarried out usually at room temperature in a nitrogen atmosphere forseveral hours. The thus-obtained ester of compound XII, the 116,170:-dihydroXy-la-chlorol,4-pregnadiene-3,20-dione 17-acylate, is recoveredfrom the reaction mixture by pouring the reaction mixture into Water andseparating the precipitated material or, alternatively, by extractingthe product with water-immiscible solvents such as benzene, ether,methylene chloride, ethylene chloride, and the like. The material thusobtained is purified through recrystallization or chromatography to givepure esters.

PREPARATION 1 6u-Flu0ro-1l'fi,21-Dilzydroxy-1,4,I 7 (20 -Pregnatrien-Five -ml. portions of a medium, containing 1% glucose, 2% corn steepliquor (60% solids) and tap water, in 250-ml. Erlenmeyer flasks, areadjusted to a pH of 4.9. This medium is sterilized for 45 minutes at 15pounds per square inch pressure and inoculated with a lto 2-dayvegetative growth of Septomyxa aflinis A.T.C.C. 6737. The Erlenmeyerflasks are shaken at room temperature (about 26 to 28 C.) for a periodof 3 days. At the end of this period this SOO-ml. volume is used as aninoculum for 10 l. of the same glucose-corn steep liquor medium which inaddition contains ml. of an antifoam compound (a mixture of lard oil andoctadecanol). The fermentor is placed into a water-bath, adjusted to 28C. and the contents stirred thoroughly (300 r.p.m.) and aerated (0.1 l.of air per minute per 1. of beer). After 20 hours of incubation, when agood growth has been developed, 1 g. of 6a-fiuoro-11B,21-dihydroxy-4,17(20)-pregnadien-3-one 21-acetate puls 0.5 g. of3-ketobisnor-4-cholen-22-al, dissolved in 16 ml. of dimethylformamide,is added and the incubation carried out at the same temperature (28 C.)and aeration for a period of 72 hours (final pH 8.3). The mycelium isfiltered and extracted with three ZOO-ml. portions of acetone. The beeris extracted with three l-liter portions of methylene chloride and theacetone extracts and the extracts of the beer are combined, dried overanhydrous sodium sulfate and evaporated. The resulting residue ispurified by chromatography over a Florisil (synthetic magnesiumsilicate) chromatographic column using Skellysolve B hexanes containingincreasing amounts of acetone to elute the column, followed byrecrystallization from acetone- Skellysolve B hexane to give6a-fluoro-11 6,21-dihydroxy- 1,4,17(20)-pregnatrien-3-one, a crystallinesolid.

PREPARATION 2 A solution is prepared containing 50 mg. of 6OL-fll10l'0-1l,8,21-dihydroxy-1,4,17 (20)-pregnatrien-3-one in 1 ml. of pyridine and1 m1. of acetic anhydride. The solution is allowed to stand at roomtemperature for a period of about 21 hours and is thereupon poured intoice water to give crystals of 6a-fiuoro-11fl,21-dihydroxy-1,4,17(20)-pregnatrien-S-one 21-acetate, which are purified by recrystallizationfrom acetone-Skellysolve B hexanes.

Other 21-acylates are prepared by allowing 6u-fiuoro-11,8,21-dihydroxy-1,4,17(20)-pregnatrien-3-one to react with theselected organic carboxylic acid, preferably a hydrocarbon carboxylicacid containing from 1 to 12 carbon atoms, inclusive, or the anhydrideor acyl halide of an organic carboxylic acid. Illustrative of thecompounds thus produced are the 21-formate, the 21-propionate, the21-butyrate, the 2l-va1erate, the 21-hexanoate, the 21-laurate, the21-trimethylacetate, the 21-isobutyrate, the 21-isovalerate, the21-tertiarybutylacetate, the ZI-(B-cyclopentylpropionate), the21-cyclohexanecarboxylate, the 2l-cyclohexylacetate, the 21-benzoate,the 21-phenylacetate, the ZI-(B-phenylpropionate), the 21-(o-, m-,p-toluate), the 21-hemisuccinate, the 21-hemiadipate, the 21-acrylate,the 21-crotonate, the 21-propiolate, the 21-(2-butynoate), the2l-undecolate, the 21-cinnamate, the 21- maleate, the 21-citroconate,and the like of 60t-fluOI'O-11B, 2 l-dihydroxy- 1,4, 17 20-pregnatrien-3-one.

If the selected acylating agent is solid, an inert solvent such astoluene, xylene, or dioxane can be added to effect dissolution and toprovide a liquid esterification medium.

If the esterifying agent is the free acid, the reaction is carried outin the presence of an esterification catalyst. If the anhydride or acidchloride is used, an organic base such as pyridine is generally used.

PREPARATION 3 1 1 8,1 6 0:,21 -Trihydr0xy-1 ,4,1 7 (20-Pregnatrien-3-One 2 1 -A cetate A mixture of 9.8 g. (0.0264 mol.) of11,8,21-dihydroxy- 1,4,17(20)-pregnatrien-3-one 2l-acetate, 2.76 g.(0.0248 mol.) of selenium dioxide, 33 ml. of water and 150 ml. ofdioxane was heated at reflux for approximately 1 hour with stirring. Thethus-obtained reaction mixture containing1lB,16a,21-trihydroxy-1,4,17(20)-pregnatrien-3- one 21-acetate Wascooled in an ice bath to about 25 C. Five grams of a filter aid(synthetic magnesium silicate) was added to the cooled reaction mixture,stirred for about minutes and filtered under vacuum through a syntheticmagnesium silicate mat. The filtrate was added to 900 ml. of methylenechloride, followed by washing with four ZOO-ml. portions of water. Theorganic phase was filtered and evaporated to a volume of about ml. andpoured onto a chromatographic column packed with 800 g. Florisil(synthetic magnesium silicate). The chromatographic column was developedby eluting with Skellysolve B hexanes containing increasing amounts ofacetone. The eluate fractions were freed of solvent and those fractionseluted with Skellysolve B hexanes containing 20 to 25% acetone werecombined and recrystallized from acetone-Skellysolve B hexanes to give6.74 g. of product melting at 17818l C. Four additionalrecrystallizations from acetone-Skellysolve B hexanes gave115,16ot,21-trihydroxy-l,4,17(20)-pregnatrien-3-one 21-acetate having amelting point of 179181 C., [oz] +83 degrees s);

max.

243 mu, a 15,600

PREPARATION 4 2 0a-Chl0r0-1 1 5,21-Dihydr0xy-1 ,4,] 6 -Pregnatrien-3-One 21 -Acetate To a stirred solution of 965 mg. (0.0025 mol.) of 115,:,21 trihydroxy-1,4,17(20)-pregnatrien-3-one 2l-acetate, 100 ml. ofmethylene chloride and 556 mg. (0.003 mol.) of tri-n-butylamine atapproximately 0 C. there was added dropwise over a 5-minute period, withcontinuous stirring, 393 mg. (0.24 mol.) of thionyl chloride, dissolvedin 25 ml. of methylene chloride, while maintaining the temperature at 0C. The thus-obtained reaction mixture comprising the 20m and 205epimeric forms of 20 chloro-l1fi,21-dihydroxy-1,4,16-pregnatrien-3-one21- acetate was stirred for 1 hour at 0 C. followed by washing withthree 20-ml. portions of dilute hydrochloric acid and four 50-ml.portions of water. The washed reaction mixture was filtered and thefiltrate obtained was evaporated to a volume of about 25 ml. and pouredonto a chromatographic column packed with 80 g. Florisil and then wettedwith Skellysolve B hexanes; The chromato a graphic column was developedby eluting with Skellysolve B hexanes containing increasing amounts ofacetone. The eluate fractions were freed of solvent and those fractionseluted with Skellysolve B hexanes containing 9 to 12% acetone werecombined. Two recrystallizations from acetone-Skellysolve B hexanes gave700 mg. of 20ccchloro-l 16,21-dihydroxy-1,4,16-pregnatrien-3-one21-acetate having a melting point of 160-161 C.,

242 mu, a 15,500

EtOH NM.

1 l trien-3-one, gives the corresponding 6a-fiuoroor 6% methyl20a-chloro-1lfi,2l-dihydroxy-l,4,16-pregnatrien- 3-one 21-acetate (orother 21-acylate).

PREPARATION 5 J I fl-H ydroxy-Z 013,21 -Ep oxy-I ,4,16-Pregnatrien-3-One (II To a solution of 2.03 g. (0.005 mol.) ofZOa-ChlOIO- 11,8,2l-dihydroxy-l,4,l6-pregnatrien-3-one 21-acetate and100 ml. of methanol, cooled in an ice-bath, was added, with vigorousswirling over about a 2-minute period, 100 ml. of 0.1 N sodium hydroxidesolution. After standing in the ice bath for an additional 5 minutes,the reaction mixture was filtered and the white crystalline precipitate,thus obtained, was collected and dried to yield 1.57 g. of a productcomprising 1lfi-hydroxy-ZDQZ1-epoxy-1,4,16- pregnatrien-3-one having amelting point of 193-203 C. The thus-obtained White crystalline productwas then dissolved in about 25 ml. of ethylene dichloride and pouredonto a chromatographic column packed with 120 g. Florisil and wettedwith Skellysolve B hexanes. The chromatographic column was developed byeluting with Skellysolve B hexanes containing increasing amounts ofacetone. The eluate fractions were freed of solvent and those fractionseluted with Skellysolve B hexanes-acetone (9:1) were recrystallized 3times from acetone to give 11fi-hydroxy-20,8,21-epoxy-1,4,16-pregnatrien-3-one, melting at 205-215C. Three additional recrystallizations from methanol did not raise themelting point of the 115- hydroxy-20,6,2l-epoxy-1,4, 16-pregnatrien-3-one which, following the methanol recrystallizations hada 70mm 242.5 mu, (1.,, 14,950

and the following analysis:

Analysis.Calcd. for C I-1 C, 77.27; H, 8.03. Found: C, 76.99; H, 8.05.

Substituting in preparation as starting material: (a) 6m fluoro20/3-chloro-1lfi,21-dihydroxy-1,4,l6-pregnatrien-3-one Ill-acetate orother 21-acylates results in 6afluoro 11,8hydroxy-20/3,21-epoxy-l,4,16-pregnatrien-3- one. (b)6a-methyl-20a-chloro-11B,21-dihydroxy-1,4,16- pregnatrien-3-one21-acetate or other 21-acylates results in 6amethyl-1lB-hydroxy-20,9,21-epoxy-1,4,16-pregnatrien-3-one.

The term other 21-acylates as used in the preceding paragraph isinclusive of 21-acylates, such as, for example, the Zl-formate, the21-propionate, the 21-butyrate, the 21- valerate, the 21-hexanoate, the21-laurate, the 21-tri methylacetate, the 21'isobutyrate, the21-isovalerate, the 21-tertiarybutylacetate, the21-(fl-cyclopentylpropionate), the 2l-cyclohexanecarboxylate, the21-cyclohexylacetate, the 21-benzoate, the 21-phenylacetate, the21-(fi-phenylpropionate), the 21-(0-, m-, p-toluate), the21-hemisuccinate, the ZI-hemiadipate, the 21-acrylate, the 21-crotonate,the 21-prcpiolate, the 21-(2-butynoate) the 2l-undecolate, theZI-cinnamate, the 2l-maleate, the 21-ci-traconate, and the like.

EXAMPLE 1 1JB,21-Dihydr0xy-16u-Chl0r0-],4,17(20) -Pregnatrien-3 OneZI-Acetaie In a dry 1 1., one-necked flask was placed 40 g. (0.555 mole)of tetrahydrofuran (freshly distilled from lithium aluminum hydride) and500 ml. of dry methylene dichloride. This solution was cooled to about 5to C. and saturated with hydrogen chloride. A solution of 6.52 g. (0.02mole) of 1l,8-hydroXy-20,21-oxido-1,4,16- pregnatrien-3-one in 100 ml.of dry methylene chloride was poured into the acidic solution and thisreaction mixture stored at about +5 C. for a period of 18 hours. Thesolvents and excess hydrogen chloride were removed in vacuo and theresidue dissolved in a mixture of 20 ml. of pyridine and 20 ml. ofacetic anhydride. After standing at about for 18 hours, the acetylationmixture was poured into 300 ml. of ice-water which was then extractedthree times with ZOO-ml. portions of methylene chloride.

. 7.1 g. of a tan colored residue.

The combined methylene chloride extracts were washed with two ml.portions of dilute hydrochloric acid and a 100 ml. portion of Water. Themethylene chlo ride extracts were dried and evaporated in vacuo, givingThis material was dissolved in 100 ml. of methylene chloride andchromatographed over a column of 700 g. of Florisil (anhydrous magnesiumsilicate) as follows: 22 fractions were taken, each fraction containing500 ml. The eluting solvent consisted of 12% acetone and 88% SkellysolveB hexanes.

All fractions were papergrammed and it was determined that the slowermoving major product, fractions 13 through 22, contained primarily thedesired product. A highly purified sample of this material, recoveredfrom the subsequent osmium tetroxide hydroxylation step melted at 187 to189 C. and had an [1x1 in chloroform -37 degrees AELOH Analysis.Calcd.for C I-1 C10 C, 68.22; H, 7.22; Cl, 8.76. Found: C, 67.81; H, 7.07; Cl,8.75.

EXAMPLE 2 6a-Flu0ro-1 1fl,2]-Dihydr0xy-16u-Chl0r0-I,4,17(20Pregnalrien-S-One 21 -A cetate In substantially the same manner given inExample 1, subjecting 60c fiuoro 11 {3-hydroxy-20B,21-oxido-1,4,16-pregnatrien-3-oue to treatment with hydrogen chloride and subsequentlyacylation with acetic anhydride resulted in Gotfiuorol6a-chloro-l113,2l-dihydroxy-l,4,17(20)- pregnatrien-3-one21-acetate of melting point 180.5 to 182 C. and rotation [0:1 inchloroform 37 degrees.

AnaIysis.-Calcd. for C H CLFO C, 65.32; H, 6.67; Cl, 8.38; F, 4.49.Found: C, 65.36; H, 6.55; CI, 8.43; F, 4.29.

EXAMPLE 3 Get-Math l-16a-Chl0r0-J ][3,2I-Dihydr0xy-1,4,I7(20)Pregnatrien-3-One 21 Acetate.

In the same manner given in Example 1 submitting 60cmethyl-llfl-hydroxy20,21 oxido-l,4,1'6-pregnatrien3- one to action by hydrogen chloride andsubsequently to acetylation with acetic anhydride results in thecorresponding compound,6a-rnethyl-16m-chloro-11,8,21-dihydroxy-1,4,17(20)-pregnatrien-3one21-acetate of melting point 191192 C. and a rotation [0:] in chloroformof 45 degrees.

AnaIysis.-Calcd. for C H ClO C, 68.80; H, 7.46; Cl, 8.46. Found: C,68.57; H, 7.38; Cl, 8.58.

In the same manner shown in Example 1, 2, or 3, but using instead ofacetic anhydride, anhydrides of other carboxylic acids, especiallyhydrocarbon carboxylic acids having from 1 to 12 carbon atoms such aspropionic anhydride, butyric anhydride, valeric anhydride, hexanoicanhydride, benzoic anhydride, phenylacetic anhydride, lauric anhydride,and the like results in the production of the corresponding 2l-ester ofthe selected 16a-chloro- 1 1B,21-dihydroxy-1,4,17 (20-pregnatrien-3-one.

EXAMPLE 4 16a-Chl0r0-JJ6J70:,21-Trihydroxy-I,4-Pregnadierte-3,20- Dione21 -A cetate (1 6a -Chl oropredizisol one Acetate) In a 100 m1.one-necked flask containing a magnetic stirring bar were placed 445 mg.(0.0011 mole) of 16mchloro 11[3,21dihydroxy-l,4,17(20)-pregnatrien-3-one Zl-acetate, 10 mg. of osmiumtetroxide, 30 ml. of tertiary butyl alcohol, 0.75 ml. of pyridine, 1.35ml. of 2 N t-butanol solution of N-methylmorpholine oxide peroxide. Thismixture was stirred at about 25 for a period of 5 hours. About 25 ml. ofa freshly prepared solution of 1% sodium hydrosulfite was then added,stirred for 5 minutes and the reaction mixture filtered. The tertiarybutyl alcohol was evaporated from the filtrate under vacuum at atemperature of about 35. The residue was taken up in about 100 ml. ofmethylene chloride, the methylene chlo- 13 ride solution washed with two50 ml. portions of water,

filtered and evaporated under vacuum to give 400 mg. of

crude product. This material Was dissolved in 20 m1. of methylenechloride and chromatographed over a column of 50 g. of Florisil(anhydrous magnesium silicate) as follows: 18 fractions were taken, eachfraction being 100 ml. The eluant used throughout consisted of 12%acetone and 88% Skellysolve B. It was determined by papergram analysisthat fraction 7 through 13 contained the desired product with fractions8, 9, and 10 being exceptionally pure. These three fractions werecombined and recrystallized four times from ethyl acetate to give pure16achloro 11 8,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione 2l-acetateof melting point 240 to 242 C. and rotation [aJ of +61 degrees inchloroform.

Analysis.-Calcd. for C H ClO C, 63.22; H, 6.69; Cl, 8.15. Found: C,63.02; H, 6.56; Cl, 8.06.

EXAMPLE 5 1 6 a-C h Zora-6 a-F luoroprednisolone A cetate In the samemanner given in Example 4, 6a-fluoro-16achloro 11 8,21dihydroxy-1,4,17(20)-pregnatrien-3-one 2l-acetate was treated withosmium tetroxide in the presence of N-methylmorpholine oxide peroxide atabout 25 for 18 hours. At the termination of the reaction, the materialwas worked up as in Example 4 to give 160:- chloro-6a-fluoroprednisoloneacetate of melting point 286 and a rotation [a] in acetone of +55degrees.

Analysis.Calcd. for C H ClFO C, 60.72; H, 6.20; Cl, 7.79; F, 3.90.Found: C, 60.45; H, 6.04; Cl, 7.87; F, 3.90.

EXAMPLE 6 6a 114 ethyl-J oa-Chloro-l 1 5,1 7 (1,2 I -Trihydrxy-1,4-Pregnadiene-3,20-Di0ne 21-Acetate (6oc-M ethyl-1 6a-Chl0r0-prednisololze Acetate) In the same manner given in Example 4 treating60cmethyl 160a -chloro-11B,2l-dihydroxy-1,4,17(20)-preg: natrien-3-one21-acetate with osmium tetroxide and N- methylmorpholine oxide peroxideresults in the corresponding 6oz methyl16a-chloro-11fi,17a,21-trihydroxy- 1,4-pregnadiene-3,20-dione,21-acetate an amorphous solid of melting point 227-230";

A 243 mp(a 14,100).

Through a solution of 300 mg. sodium carbonate in 10 ml. of 95% ethanolwas passed a stream of nitrogen for a period of 10 minutes. To thissolution was added a solution of 300 mg. of 16a-fluoroprednisoloneacetate in ml. of ethanol similarly purged with a stream of nitro gen.The mixture was. allowed to stand at room temperature under nitrogen fora period of 6 hours, then poured into 100 ml. of water and neutralizedby the addition of 5% hydrochloric acid. The mixture was extracted with3 portions of 25 ml. of methylene chloride, the methylene chlorideextracts were combined, washed with water, dried and evaporated. Thematerial thus obtained was recrystallized 3 times from methanol andSkellysolve B hexanes to give 16a-chloroprednisolone.

In the same manner described in Example 7, by sub-- jecting tosaponification in a nitrogen atmosphere, 6amethyl-l6a-chloroprednisoloneacetate or 6a-fluOI0-16achloroprednisolone acetate, the correspondingfree alcohols, 6a-methyl-16a-chloroprednisolone and6u-fluorol6a-chloroprednisolone are obtained and can be isolated byextraction method in conventional known manner.

EXAMPLE 8 16a-Chl0r0-11/3,1 7a,2]-Trihydr0x v-1,4-Pregnadiene-3,20-

Dione 21 B Cyclopentylpropzonate) [16u-Chl0r0- prednisolone21-(/3-Cycl0pentylpropionate)] EXAMPLE 96a-Flu0r0-1oa-chloroprednisolone 21 -Phenylpropi0nate A mixturecontaining 200 mg. of 6a-fluoro-16u-chloroprednisolone in 2 ml. ofphenylpropionic anhydride and 1 ml. of pyridine was allowed to stand atroom temperature for a period of 6 hours and was thereupon poured into 6ml. of ice water. The aqueous solution was allowed to stand for 24hours, whereupon it was extracted with three 15-ml. portions ofmethylene chloride. The methylene chloride extracts were combined,washed, dried over anhydrous sodium sulfate and evaporated. The thusobtained residue was recrystallized 4 times from methanol to give pure6a-fiuoro-16a-chloroprednisolone 21' phenylpropionate[6a-fluoro-l6a-chloro-l1,8,17a,21- trihydroxy 1,4 pregnadiene-3,20-dione2l-phenylpropionate].

In the same manner as shown in Examples 8 and 9, other esters of16a-chloroprednisolene, Got-flHOI'O-lGotchloroprednisolene, and6a-methyl-16u-chloroprednisolene can be prepared by reacting thebefore-mentioned free alcohols with acid anhydrides or acid chlorides ororganic carboxylic acids, preferably hydrocarbon carboxylic acidscontaining from 1 to 12 carbon atoms. Representative esters thusobtained include the formate, acetate, propionate, butyrate, valerate,hexanoate, heptanoate, octanoate, nonate, decanoate, undecanoate,laurate, benzoate, phenylacetate, phenylpropionate,cyclopentylpropionate, tertiary butylacetate, acrylate, crotonate,cinnamate, cyclohexylcarbonate, and the half esters of succinic, maleic,adipic or [3,B-dirnethylglutaric acid and the like ofl6a-chloroprednisolene, 6u-methy1-16a-chloroprednisolone,6a-fluoro-16achloroprednisolone.

EXAMPLE 10 9aFluoro-J6u-Chl0r0-l15,1704,21-Trihydr0xy-],4-Pregnadiene-3,20-Di0ne21-Acetate (9wFlu0r0-16u-Chlorm prednisolone 2] -A cetate) To a stirredsolution of 590 mg. (0.00135 mole) of 16a-chloro11B,17a,2l-trihydroxy-1,4-pregnadiene-3,20- dione ZI-acetate in 8 ml. ofpyridine was added 316 mg. of N-bromoacetarnide. The solution wasstirred at 25 for a period of 20 minutes and then cooled to 10 andmaintained at this temperature while saturating with sulfur dioxide. Thesulfur dioxide was passed as a stream of gas over the surface of thestirred reaction mixture. Thereupon ml. of water was added and the solidprecipitate collected on a filter. The precipitate was washed on thefilter with water and then dried. The crude product, thus obtained, waspurified by chromatography over 50 g. of Florisil (anhydrous magnesiumsilicate) by eluting with 12% acetone and 88% Skellysolve B hexanes. Thethus-obtained purified material was 16a-chlO10-17oc,21-dihydroxy-1,4,9(11)-pregnatrien-3,20-dione 21 acctate which was usedin the subsequent step without further purification.

To a stirred solution of 474 mg. (0.00113 mole) of crude 16oc-Chl01'0-17a,21-dihydroxy-1 ,4,9 11 -pregnatriene-3,20-dione ZI-acetate in 32 ml.of tertiary butyl alcohol and 8 ml. of methylene chloride was added amixture of 1.45 ml. of 70% perchloric acid in 10 ml. of water and asolution of 186 mg. of N-bromoacetamide in 6 ml. of tertiary butylalcohol. After stirring the reaction mixture for minutes at about 25 C.a solution of 266 mg. of sodium sulfite in 15 ml. of water was added.This mixture was then concentrated under reduced pressure to a volume ofabout ml. and then diluted with 100 ml. of water and filtered. The dry,white precipitate, thus obtained, weighed 594 mg. This material,16mchloro-9a-bromo 11fl,17oc,21 trihydroxy-1,4-pregnadiene-3,20-dione21-acetate, was used in the following step without further purification.

A mixture of 594 mg. (0.00113 mole) of l6u-Chl0l0- 9a-bromo 11/3,17oz,21trihydroxy-1,4-pregnadiene-3,20- dione 2l-acetate, 750 mg. of potassiumacetate and 50 ml. of acetone was stirred and heated at reflux for 20hours. The reaction mixture was then evaporated to dryness under reducedpressure and the residue extracted with methylene chloride. The extractwas concentrated to a volume of about 20 m1. and poured onto achromatographic column of 60 g. of Florisil (anhydrous magnesiumsilicate) and eluted with a mixture of 12% acetone and 88% Skellysolve Bhexane. Evaporating the eluant yielded 368 mg. of16oz-chloro-9/3,11,8-epoxy-17a,21-dihydroxy-l,4-pregnadiene-3,20-dione2l-acetate which was used in the next step without further purification.

To 11.9 g. of hydrogen fluoride contained in a polyethylene bottle andcooled in a Dry-Ice alcohol bath, was added 21 ml. of coldtetrahydrofuran and then a cold solution of "368 mg. (0.000846 mole) ofl6oc-Cl1lOIO-9B,l1aepoxy-l7a,2l-dihydroxy-1,4-pregnadiene-3,20 dione 21-aceta-te, dissolved in 20 ml. of methylene chloride. The mixture wasstirred at about 5 for 20 hours and then cantiously poured into anice-cold solution of 57 g. of sodium carbonate in 1 l. of water. Theaqueous solution was extracted with four 100-ml. portions of methylenechloride and these extracts combined, dried and evaporated to a volumeof about 20 ml. This crude solution was poured onto a chromatographiccolumn containing 50 g. of Florisil' (anhydrous magnesium silicate) andthe product eluted with a mixture of 15% acetone and 85% Skellysolve Bhexanes. The fractions containing the product, as determined by paperchromatography, were combined and recrystallized from ethyl acetate toyield 201 mg. (32.8% yield) of 9zx-fiHOI0-16u-Chl0IO-11B,l7oc,2ltrihydroxy-1,4-pregnadiene-3,20-dione 2lacetate of melting point 246 to247 C. and rotation [cab in chloroform +61 degrees.

Analysis.Calcd. for C H ClFO C, 60.72; H, 6.20; CI, 7.79; F, 4.18.Found: C, 60.46; H, 6.15; Cl, 7.75; F, 4.18.

EXAMPLE 11 6 m,9a-Diflu0ro-1 6 qc-ChlOrO-Z 118,1 7a,21-Trihydroxy- 1,4-Fregnadiene-3,ZO-Dione 21 -A cetate To a stirred solution of 520 mg.of 6a-fluoro-16a-chloroprednisolone 2'1-acetate in 5 ml. of pyridine wasadded 280 mg. of N-bromoacetamide. The solution was stirred at C. forabout 20 minutes and then cooled to 10 C. and maintained at thistemperature, while a stream of sulfur dioxide is passed over the surfaceof the stirred reaction mixture. Water (100 ml.) was added and the solidprecipitate collected on a filter, washed with water and dried. Thecrude product, 6oL-fil10IO-16oc-Chl01'0- 11,21-dihydroxy-1,4,9(l1)-pregnatriene-3,20-dione 21- acetate, weighed520 mg.a 100% crude yield.

' To a stirred solution of 520 mg. of crude 6ix-fluoro-16achloro 170:,21dihydroxy-1,4,9(11)-pregnatriene-3,20 dione, 21-acetate, dissolved in 34ml. of tertiary butyl alcohol and 8 ml. of methylene chloride, was addeda mixture of 1.53 ml. of 70% perchloric acid in 10.5 ml. of water and asolution of 195 mg. of N-bromoacetamide in 6.3 ml. of tertiary butylalcohol. After stirring for 15 minutes at about 25, a solution of 280mg. of sodium sulfite in 15.8 ml. of water was added, the mixtureconcentrated under reduced pressure to a volume of about 20 ml., dilutedwith 100 ml. of water and filtered. The dried, white precipitate,6a-fluoro-9a-bromo-1Got-chloro-11,8,17ix,21-trihydroxy-1,4-pregnadiene-3,20-dione, 21-acetate, weighed574 mg.a crude yield.

A mixture of 574 mg. of crude 6OL-fiuOrO-9OL-bl'OmO-16a-chloro-11/3,17a,21-trihydroxy-1,4-pregnadiene 3,20- dione,'Zl-acetate, 713 mg. of potassium acetate and 50 ml. of acetone wasstirred and heated at refiux for 20 hours. The mixture was thenevaporated to dryness under vacuum and the residue extracted withmethylene chloride. The extract was concentrated to a volume of about 20ml. and poured onto a chromatographic column of 60 g. of Florisil(anhydrous magnesium silicate). The eluting solvent was 12% acetone88%Skellysolve B and ml. fractions were taken. Fractions 3 through 8contained the desired product, 6oc-llll0lO-16oz-Chl0lO-9B,l1}8epoxy-17a,2 l-dihydroxy-l,4-pregnadiene-3,20 dione 21-acetate, andthe combined weight of these evaporated fractions was 400 mg.an 82%column yield.

To 11.9 g. of hydrogen fluoride contained in a polyethylene bottle andcooled in a Dry-Ice alcohol bath, was added 21 ml. of coldtetrahydrofuran and a cold solution of 400 mg. of6ot-fluoro-16a-chloro-9BA1B-epoxy-l7a,21-dihydroxy-l,4-pregnadiene-3,20-dione Zl-acetate in 20 ml. of methylenechloride. The mixture was stirred at about 5 for 20 hours and thencautiously poured into an icecold solution of 57 g. of sodium carbonate,dissolved in l l. of water. The aqueous solution was extracted with four100-ml. portions of methylene chloride and these extracts combined,dried and evaporated. The residue was an amber mush, which upon theaddition of 10 ml. of methylene chloride followed by stirring andfiltration yielded 217 mg. of a white solid. This crude product wasdissolved in 100 ml. of ethylene chloride and poured onto achromatographic column containing 100 g. of Florisil (anhydrousmagnesium silicate) and the product eluted with 100-ml. portions of 17%acetone'83% Skellysolve B (Fractions 1-18) and 20% acetone80%Skellysolve B (Fractions 19-29). Fractions 10' through 29 contained theproduct and were combined to yield 174 mg. of material (41.6%).Recrystallization from ethyl acetate yielded 6a,9x-difiuoro-16a-chloro-l1,8,17a,21-trihydroxy-l,4-pregnatriene-3,20-dione2l-acetate which decomposed at 291 and had the following analysis:

Analysis.-Calcd. for C23H2qclF2O5I C, 58.41; H, 5.76; F, 8.04; Cl, 7.50.Found: C, 58.49; H, 5.90; F, 7.73; Cl, 7.55.

EXAMPLE 12 6 a-Methy l-9a-Flu0r0-1 6a-Chl0ro-1 1,8,1 7u,2l -Trihydr0xy-1 ,4-Pregnadiene-3,20-Di0ne 21 -A estate In substantially the samemanner shown in Example 10, 601-[1'16ihYl-160L-Chl0i0 11fi,17x,21trihydroxy 1,4- pregnadiene-3,20-dione 21-acetate, is dehydrated at the9,1l-positions with N-bromoacetamide followed by treatment with sulfurdioxide to give 6a-methyl-l6a-chloro- 17a,21-dihydroxy-1 ,4,9( 1 1-pregnatriene-3,20-dione 21- acetate.

This product was treated with N-bromoacetamide and perchloric acid intertiary butyl alcohol to give 6a-methyl-9u-bromo-16ix-chloro-11B,17a,21-trihydroxy-1,4 pregnadiene-3,20-dione21-acetate.

The thus-obtained product was treated with sodium acetate in acetone atreflux temperature to give 6u-methyl- 16a-chloro-9fi,l13-epoxy-17u,21-dihydroxy 1,4 pregnadiene-3,20-dione ZI-acetate.

The thus-obtained epoxy compound was treated with hydrogen fluoride inmethylene chloride containing tetrahydrofuran to give6oc-fllsthYl-9oc-flll0r0-16oc-ChlOIO-llfi,17a,2l-trihydroxy-l,4-pregnatriene-3,20-dione Zl-acetate.

EXAMPLE 13 9u-Fluor0-16a-Chloroprea'nisolone Through a solution of 500mg. sodium carbonate in '10 ml. of 95% ethanol was passed a stream ofnitrogen for a period of minutes. To this solution was added a solutionof 300 mg. of Qua-fluoro-l6a-chloroprednisolone acetate in 5 m1. ofethanol similarly purged with a stream of nitrogen. The mixture wasallowed to stand at room temperature under nitrogen for a period of 6hours, then poured into 100 ml. of water and neutralized by the additionof 5% hydrochloric acid. The mixture was extracted with three 25-ml.portions of methylene chloride, the methylene chloride extractscombined, washed with Water, dried and evaporated. The material thusobtained was recrystallized 3 times from methanol and water to give9a-fluoro-l6a-chloroprednisolone.

In substantially the same manner described in Example 13, by subjectingto saponification in a nitrogen atmosphere6a-methyl-9a-fluoro-16a-ch1oroprednisolone acetate or6a,9a-difluoro-l6a-chloroprednisolone acetate, the corresponding freealcohols, 6a-methyl-9a-fluoro-l6achloroprednisolone and6a,9a-difluoro-l6a-chloroprednisolone, are obtained, and are isolated bymethods known in the art.

EXAMPLE =14 Qa-Fllloro-I 6a-Chl0r0-1l 5,1 7 0:,21 -Trihydr0xy-1 ,4Pregnadz'ene-3,20-Di0ne 21 -(/8-Cycl0pentylpropionate) [90:- F luoro-I6u-Chl0r0prednis0l0ne 21 ,B-Cyclopentyl propionate) A mixture containing200 mg. of 9oL-fiIlOIO-l6oc-Chl0f0- prednisolone, 2 ml. offi-cyclopentopropionyl chloride and 2 m1. of pyridine was allowed tostand at room temperature for 4 hours and then poured into 50 ml. ofwater. The aqueous reaction mixture was allowed to stand overnight andwas thereupon extracted with three =l0-ml. portions of methylenechloride. The methylene chloride extracts were combined, evaporated andthe residue recrystallized 4 times from methyl alcohol to give90c-flll0l0- 16a chloroprednisolone 21-(B-cyclopentylpropionate).[9a-fluoro-16a-chloro-l1,8,l7a,2l-trihydroxy 1,4 pregnadiene-3,20-dione21-(fi-cyclopentylpropionate) 1.

EXAMPLE 6a,9a-Difluoro-l 6a-Chlor0prednz's0l0ne 21 -Phenylacemte Amixture containing 200 mg. of 6u,9u-difiuoro-16uchloroprednisolone in 2ml. of phenylacetic anhydride and 1 ml. of pyridine was allowed to standat room temperature for a period of 24 hours and then poured into 50 ml.of ice water. The aqueous solution was allowed to stand for 24 hours andthen extracted with three lS-ml. portions of methylene chloride. Themethylene chloride extracts were combined, washed, dried over anhydroussodium sulfate and evaporated to give a residue. The thus-obtainedresidue was recrystallized 4 times from methanol to give pure6a,9u-difluoro-l6u-chloroprednisolone 21- phenylacetate[6a,9ot-diflll0IO-l6oc-Chl0f0 llfi,l7a,21-trihydroxy-l,4-pregnadiene-3,20-dione 21-phenylacetate].

EXAMPLE =16 In substantially the same manner given in Example 14,9u-fluoro-l6a-chloro-l1B,17a,21-trihydroxy-l,4 pregnadiene-3,20-dione inpyridine solution was reacted:

(a) with propionyl chloride to yield 9ot-fl1l010-16uchloro-l1fi,17a,21trihydroxy !1,4 pregnadiene 3,20- dione 2l-propionate;

(b) with butyryl chloride to yield 9a-flu0IO-16oa-Chl0l0-11B,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-butyrate;

(c) with benzoyl chloride to yield 9ot-fl1l010-16cc-Chl010- 1l5,l7a,21-trihydroxy-1,4-pregnadiene 3,20 dione 21- benzoate;

(d) with lauryl chloride to yield 9a-fluoro-l6a-chloro-11,8,1701,2l-trihydroxy-1,4-pregnadiene 3,20 dione 21- laurate;

(e) with crotonyl chloride to yield 9a-fll1OIO-l6achl0ro'l1fi,17u,2ltrihydroxy 1,4-pregnadiene 3,20- dione 2J1-crotonate;

(f) with acrylyl chloride to yield 9u-fluoro-l6oz-ch1oro- 11/3,17a,21trihydroxy 1,4 pregnadiene 3,20-dione 2l-acrylate; 1

(g) with tertiary butylacetyl chloride to yield 9oc-fl11010- 16cc chlorol1fl,-17a,2l trihydroxy 1,4 pregnadiene- 3,20-dione 21-tertiarybutylacetate.

EXAMPLE 17 In substantially the same manner given in Example 15,6a,9a-difiuoro-16a chloro 1lfi,l7oc,2l trihydroxy 1,4-preflgnadiene-3,20-dione in pyridine solution was reacted m (a) aceticanhydride to give 6a,9a-difluoro-l6a-choro- 1l5,17a,2l-trihydroxy-l,4-pregnadiene-3,20-dione 2l-acetate;

(b) valeric anhydride to give60,9oL-diflL1OIO-16otchloro-l15,17a,21-trihydroxy-1,4-pregnadiene-3,20dione 21-valerate;

(c) hexanoic anhydride to give6a,9oc-diflu0rO-16otchloro-l1,8,17a,21-trihydroxy-1,4-pregnadiene-3,20dione 2l-hexanoate;

(d) phenylpropionic anhydride to give 6a,9a-difluor0-l6a-chloro-11B,17a,21-trihydroxy-l,4-pregnadiene 3,20- dione21-phenylpropionate;

(e) decanoic anhydride to give6a,9a-difluoro-l6uchloro-l113,l7a,2l-trihydroxy-1,4-pregnadiene-3,20dione ZI-decanoate;

(f) succinic anhydride to give60,9ot-diflUOIO-l6achloro-llfi,l7a,2l-trihydroxy-1,4 pregnadiene 3,20dione ZI-hemisuccinate;

(g) maleic anhydride to give 6a,9a-difluoro-16achloro-l1p,l7a,21-trihydroxy-l, 4-pregnadiene 3,20 dione ZI-hemimaleate;

(h) B,fi-dirnethylglutaric anhydride to give 6ot,9oz.-dl-'fiuoro-16a-chloro-11B,17a,21-trihydroxy 1,4 pregnadiene-3,20-dione21-5,;3-dimethylglutarate.

EXAMPLE 18 In substantially the same manner given in Example 15,6a-methyl-9a-fluoro-l6a-chloro 115,17 a,21 trihydroxy-1,4-pregnadiene-3,20-dione in pyridine solution was reacted with:

(a) butyric anhydride to give6u-methyl-9a-fluoro-l6achloro-l1B,1711,21-trihydroxy-1,4-pregnadiene-3,20dione ZI-butyrate;

(b) propionic anhydride to give 6a -methyl-9a-fluoro-16a-chloro-1lB,l7oc,2l-trihydroxy-1,4 pregnadiene 3,20- dione21-propionate; i

(c) Valerie anhydride to give6a-methyl-9a-fluoro-16achloro-l1,8,l7a,2l-trihydroxy-l,4-pregnadiene-3,20dione 21-valerate;

(d) hexanoic anhydride to give 6a-methyl-9a-fiuoro-16a-chloro-11p,17a,21-trihydroxy-1,4 pregnadiene 3,20- dione21-hexanoate;

(e) octanoic anhydride to give 6a-methyl-9u-fluoro-16oc-ChlOIO-1lfi,17a,21-trihydrOXy-1,4 pregnadiene 3,20- dione2l-octanoate;

(f) lauric anhydride to give 6a-methyl-9u-fluoro l6achloro-llfi,l7x,2l-trihydroxy 1,4-pregnadiene 3, 20 dione 2l-laurate;

(g) benzoic anhydride to give 6a-methyl-9a-fluoro-16achloro-l1B,17a,2l-trihydroxy-l,4-pregnadiene-3,20 dione 21-benzoate; i i

(h) phenylpropionic anhydride to give 6a-methyl-9afiuoro-16a-chloro-l lB,17a,21 trihydroxy 1,4 pregnadiene-3,20-dione 2-phenylpropionate; V p 3(i) cinnamic anhydride to give 6a-methyl-9a-fluoro- 16a-chloro-11,8,17a,21-trihydroxy-l,4 pregnadiene 3,20-'

(k) succinic anhydride to give 6a-methyl-9cx-fiuoro-'16avchlor'o-11/8,17-a,21-trihydroxy-1,4 pregnadiene 3,20- dion'e21-hem'isuccinate;

(l) maleic anhydride to give6a-methyl-9a-fluoro-l6aichlo'ro-llfifl7a,2l-trihydroxy-1,4-pregnadiene-3,20dione 21-hernin1aleate.

In substantially the same manner as shown in Examples 14 and 15, otheresters of 9iz-fiuo'ro-l'6a-chloroprednisolone,6a,9a-difluoro-l6ot-chloroprednisolone, and6a-methyl-9a-fluoro-l6a-chloroprednisolone can be prepared by reactingthe before-mentioned free alcohols with acid anhydrides or acidchlorides of organic carboxylic acid, preferably hydrocarbon carboxylicacids containing from 1 to 12 carbon atoms. Representative esters thusobtained include the isobutyrate, tertiarybutylacetate, valerate,hexanoate, heptanoate, cyclohexylcarboxylate, octanoate, nonate,decanoate, undecanoate,-laurate, benzoate, phenylacetate,phenylpropionate, cyclopentylpropionate, crotonate, acrylate, butynoate,cinnamate, undecylate, and the half esters of succinic, maleic,'fi,fidimethyl-glutaric acid, and the like. I

Alternatively, the synthesis of 6oc-flll0rO-l6oc-Chl0r0- prednisolone,and 6a-methyl-1oa-chloroprednisolone can be carried out in a reversedorder of steps as shown in the example below.

EXAMPLE 20 6a Fluoro 16cc Chloro 115,17a,21 Trihydroxy 1,4-Pregnadiene-3,20-Dipize 21 Acetate (6a Fluoro 16a- Cliloroprednfsolone21-Acetate).

In a -1. three-neck flask fitted with a stirrer, gas inlet tube and adrying tube were placed 3 Lot methylene chloride and 225 ml. of freshlydistilled tetrahydrofuran. This solution was cooled to about andsaturated with gaseous hydrogen chloride.fia-fluoro-l1B-hydroxy-20,3,21- oxido-4,16-pregnadien-3-one (36 g.-0.104mole) was dissolved in 500 ml. of methylene chloride and poured into theacidic solution. The reaction mixture was stirred at a pot temperatureof about 10 for 18 hours. The solvent, tetrahydrofuran and excess acidwere then evaporated under vacuum at a pot temperature of less than 40.The crude residue was dissolved in a solution made up of 110 ml. ofpyridine and 11.0 ml. of acetic anhydride. After standing overnight atabout 25, the solution was poured into 3 l. of ice water, extracted withmethylene chloride and the combined extracts washed with dilutehydrochloric acid and then water. Evaporation of themethylene chlorideleft a residue of 30 g. of crude product. This material was purified bychromatographing over 800 g. of Florisil. The eluting solvent was 10%acetone-90% Skellysolve B and 535-m1. fractions were collected. Twoproducts were obtained as determined by papergram analysis. The leastpolar of these two materials (fractions 10 through 22) was20-chloro-6a-fluoro-2l-acetoxy-ll e-hydroxy-'4,17(20)-pregnadien-3'-one.The more polar material (fractions 26 through 31) wasl6-chloro-6u-fiuoro- 21-acetoxy-l118-hydroxy 4,17( 20) pregnadien 3 one.During a subsequent preparation of the desired compound, a portion ofthe column fractions containing the more polar material wasrecrystallized four times from acetone and gave the following physicalconstants: M.P. 164166; and rotation [04] CHCl 5 degrees.

Analysis.Calcd. for C H ClFO C, 65.01; H, 7.12; Cl, 8.34; F, 4:47.Found: C, 65.37; H, 7.17; Cl, 8.88; F, 4.51.

6cz-flu010-1 1fi-hydroxy-20,21-oxido-4, 16' pregnadien-3- one wasprepared from 6e-fiuoro-11B,21-dihydroxy-4, 17-(20)-pregnadien-3-one2l-aceta-te in the following mam ner:

A mixture of 0.5 g. of 6u.-fluoro-11fi,21-dihydroxy- 4,17(20)-pregnadien-3-one ZI-acetate, 0.2 g. of selenium dioxide, 10 ml. ofdioxane and 2 ml. of water was heated under reflux for approximately onehour with stirring. The solvent was then distilled in vacuo to give aresidue. The thus-obtained residue was dissolved in methylene chloride,washed with water and dried over anhydrous sodium sulfate. The driedmethylene chloride solution was then poured onto a 40 g. Florisil(synthetic magnesium silicate) chromatographic column. Thechromatographic column was developed by eluting with commercial hexanescontaining increasing amounts of acetone. The eluate fractions werefreed of solvent and the fractions eluted with commercial hexanescontaining 30% acetone gave 220 mg. of product which was recrystallizedtwice from ethyl acetate to yield Got-fluoro- 116,16o ,21 -'trihydroxy4,17(20) pregnadien 3 one 21-acetate having a melting point of l-187 C.,[a] |-l05 degrees (CHCI and the following analysis:

An alysis.Calcd. for C H FO C, 67.95; H, 7.69; F, 4.67. Found: C, 68.04;H, 8.04; F, 4.70.

To a solution of 32 g. of 6a-fluoro-11j3,16e,21-trihydroxy-4,17(20)-pregnadien-3-one 21-acetate in 915 ml. of methylene chloride containing19.4 ml. of tri-n-butylamine cooled to 0 C. there was added 5.4 ml. ofthionyl chloride over a period of 5 minutes. The reaction mixture wasstirred at 05 C. for 30 minutes and then washed twice with dilutehydrochloric acid and once with water. The washed solution was thendried over sodium sulfate and poured onto a 2 kg. Florisilchromatographic column. The chromatographic column was de veloped byeluting with commercial hexanes containing increasing amounts ofacetone. The eluate fractions were freed of solvent and those fractionseluted with commercial hexanes containing 15% acetone were combined toyield 15.1 g. of a product comprising 200:- chloro 60c fluoro 115,21dihydroxy 4,16 pregnadien-3-one 2l-acet ate, which was used withoutfurther purification.

A portion of the thus-obtained product was recrystallized from ethylacetate-commercial hexanes to yield ZOa-chloro-Ba. fluoro 11 9,21dihydroxy 4,16 pr'e'gnadien-S-one ZI-acetate having a melting point of158- 160 C. and the following analysis:

Analysis.+Calcd. for C H ClFO C, 65.07; H, 7.12; CI, 8.35; F, 4.48.Found: C, 65.08; H, 7.09; Cl, 8.55; F, 4.71.

20,9 chloro 6oz fluoro 115,21 dihydroxy 4,16-

pregnadien-3-one 2l-acetate is present in the mother liquor and can berecovered by further chromatography or countercurrent extractionfollowed by recrystallization.

767 mg. of the product comprising ZQa-ChlOl'O-fiafluoro 115,21 dihydroxy4,16 pregnadien 3 one ZI-acetate, was dissolved in 60 ml. of methanolcontaining 20 ml. of N/lO sodium hydroxide. The reaction mixture wasmaintained at about 26 C. for approximately 10 minutes after which timethe excess alkali was neutralized by the addition .of 1.7 ml. of N/10hydrochloric acid. A residue crystallized following distillation invacuo of most of the solvent from the neutralized solution. Thethus-obtained residue was recrystallized from ethyl acetate-commercialhexahes to give 300 mg. of a product having a melting point of 140l46 C.Two further recrystallizations from ethyl acetatecommercial hexanesyielded 6a-fluoro-1lfi-hydroxy-ZO/S, 21-epoxy-4,16-preg:nadien-3onehaving a melting point of l52154' C., [a] +189 degrees (CHCl and thefollowing analysis: v

Analysis.-Calcd. for 0 11 170,: C, 72.80; H, 7.86; F, 5.48. Found: C,72.88; H, 7.78; F, 5.34.

60: fluoro 11,8 hydroxy 2011,21 epoxy 4,16- pregnadien-3-one is presentin the mother liquors and can be recovered by further chromatography orcountercurrent extraction followed by recrystallization.

A mixture of 3.4 g. (0. 00795 mole) of 16a-chloro 6a fluoro 115,21dihydroxy 4,17(20) pregnadien- 3-one 2l-acetate, 1.66 g. of seleniumdioxide, 5.1 m1. of pyridine and ml. of tertiary butanol was stirred andheated at reflux for about '18 hours. After filtering and evaporatingthe solvent under vacuum the residue was dissolved in about 100 ml. ofmethylene chloride and washed with dilute hydrochloric acid and water.The organic phase was evaporated to dryness under vacuum, leaving aresidue weighing 1.84 g. This crude product was chromatographed over 200g. of Florisil. The eluting solvent was 12% acetone88% Skellysolve B;200-1111. fractions were collected. Fractions 13 through 19 containedthe desired product, 565 mg.a 17% yield of 16a chloro 6oz fluoro 11 8,21dihydroxy 1,4, 17(20)-pregnatrien-3-one of melting point 180.5-182";rotation [111D CHCl 37 degrees.

A solution of 565 mg. (0.00133 mole) of l6a-chloro- 6a fluoro 11,8,21dihydroxy 1,4,17(20) pregnatrien- 3-one 21-acetate, osmium tetroxide (12mg), pyridine (1 m1.), tertiary butanol (50 ml.) and 1.63 ml. of a 2.0 Ntert. butanol solution of N-methylmorpholine oxide peroxide was stirredat about 25 for about 18 hours. Ten milliliters of a 1% sodiumhydrosulfite solution was added, stirred 10 minutes and the mixturefiltered through a mat of Magnesol. Evaporation of the filtrate undervacuum yielded 409 mg. of crude product which was chromatographed over50 g. of Florisil. The eluting solvent was 12% acetone-88% Skellysolve Bhexanes; 100-ml. fractions were collected.

Fractions 11 through 17 contained the desired material, Tollenspositive, 16a-chloro-6cc-fiuoroprednisolone ac etate. Since thesefractions were small and still contained starting material, the processwas repeated on a larger scale using 5.04 g. of starting material. Theproduct was worked up as described before and recrystallized from ethylacetate to give about 17% of the desired product16a-chloro-6a-fluoroprednisolone acetate of melting point 286 C. androtation [ed in acetone of +55 degrees.

EXAMPLE 21 l6a-Chl0r0-21Jada-11517u-Dihydr0xy-1,4 Pregnadiene-iZO-DioneA solution of one gram of Mot-chloroprednisolone, dissolved in sevenmilliliters of pyridine, was cooled to zero degrees and 0.4 milliliterof methanesulfonyl chloride was added with stirring. After stirring fora period of two hours at C., 40 ml. of water was added. The precipitatewas collected on a filter paper, washed with water and air dried to givea white powder, 16a-chloroprednisolone 21-methanesulfonate.

A solution of 1 g. of crude 21-rnethanesulfonate of160c-Chl010p1'6d1'118010116, dissolved in 20 ml. of boiling acetone, wastreated with one gram of sodium iodide in 50 ml. of acetone. The mixturewas stirred at the boiling point for a period of 15 minutes and thenconcentrated to approximately one half volume. After cooling to roomtemperature, a cold solution of 0.2 gram of sodium thiosulfate in 40 ml.of water was added. The mixture was further chilled to a temperature ofabout and then filtered. The ivory-colored, crystalline product, 160:-chloro 21 iodo-11B,17a-dihydroxy-1,4-pregnadiene-3, 20-dione was washedwith water, dried and used without further purification for thepreparation of the 21-desoxy steroid and the preparation of thephosphate of 16a-chloroprednisone.

In the same manner given in Example 21, 6a-fluoro- 16achloroprednisolone, 6a-methyl-Mot-chloroprednisolone,9a-fiuoro-Mot-chloroprednisolone, 6a,9a-difluoro- 16a-chloroprednisoloneand Goa-HlflthYl-9a-fill0l0-16a-Cl1l0 roprednisolone can be convertedwith methanesulfonyl chloride, ethanesulfonyl chloride, propanesulfonylchloride, toluenesulfonyl chloride or benzensulfonyl chloride to theirrespective 21-esters, namely the ZI-methanesulfonate,ZI-ethanesulfonate, ZI-propanesulfonate, 21-toluene sulfonate or21-benzenesulfonate of 6a-fluoro-16achloroprednisolone, 6ozmethyl-16a-chloroprednisolone, 9oz fluoro Mix-chloroprednisolone,16OL-Ch1OIOPICdI1lSO- lone, 6a,9a-difluoro-16a-chloroprednisolone andGet-methyl-9a-fluoro-16a-chloroprednisolone which are isolated EXAMPLE22 16a-Chl0ro-l113,17a-Dihydr0xy-J,4-Pregi1adiene- 3,20-Di0ne Twohundred milligrams of crude6oc-ChloI0-11,B,17ocdihydroxy-Zl-iodo-1,4-pregnadiene-3,20-dione wasslurried with 5 ml. of acetic acid and stirred for a period of 45minutes. An aqueous solution of 250 mg. of sodium thiosulfatepentahydrate was added until the iodine color disappeared. Additionalwater was added (50 ml.) and the mixture extracted with three 25-ml.portions of methylene chloride. The methylene chloride extracts werecombined, washed with water and cold sodium bicarbonate solution untilall acetic acid was neutralized. After drying over anhydrous sodiumsulfate, the solution was concentrated to approximately 15 ml. andchromatographed by eluting with increasing proportions of acetone inSkellysolve B hexanes over 10 g. of Florisil (synthetic magnesiumsilicate). Fractions of 50 ml. were taken. The fractions containing the16a-chloro-llfi,17a-dihydroxy- 1,4-pregnadiene-3,20-dione, as determinedby papergrarn analyses, were combined and evaporated to give a residuewhich was recrystallized 3 times from methanol. The thus-obtainedproduct was 16a-chloro-11fi,17a-dihydroxy- 1,4-pregnadiene-3,20-dione.

In the same manner, dehalogenating with sodium or potassium thiosulfateor other reducing agents such as zinc and acetic acid, sodium orpotassium sulfites or bi sulfites, other 2l-iodo compounds such as: 9stfluoro 16oz chloro-l1B,17u-dihydroxy-21-iodo-l,4-

pregnadiene-3,20-dione; 6a fluoro16a-chloro-11/3,17a-dihydroxy-21-iodo-1,4-

pregnadiene-3,20-dione;

60:,90: difluoro 16a-chloro-11/8,l7u-dihydroxy-21-iodo-1,4-pregnadiene-3,20-dione;

6a-methy1-16a-chl0ro-1 1/5',17a-dihydroxy-21-iodo-1,4-

pregnadiene-3,20-dione;

6u-methyl-9a-fluoro- 1 60L-Ch101'O-1 1B,17u-dihydroxy-21-iodo-l,4-pregnadiene-3,20-dione are converted into the corresponding21-methyl steroids,

9u-flu0ro-16a-chloro-1 1,8,17a-dihydro-1,4-pregnadiene- 3,20-dione;

6a-methyl-16a-chloro-1 15,17a-dihydro-1,4-pregnadiene- 3,20-dione;

6a-methyl-9a-fluoro-16a-chloro-1 1,8, 17a-dihydro-1 ,4-

pregnadiene-3,20-dione.

EXAMPLE 23 16a-Chl0ro-11,8,170,2]-Trihydroxy-J,4-Pregnadiene-3,20- Dione2] -Dihydrogen Phosphate (16u-Chl0r0-Prednis0- Zone 21-Dihydr0genph0sphate) Silver dihydrogen phosphate was prepared by thereaction of trisilver phosphate with phosphoric acid in stoichiometricquantities. A mixture was prepared containing 20 m1. of acetonitrile, 2g. of silver dihydrogen 23 phosphate, and 1 g. of16u-chloro-21-iod0-11fl,17m-dihydroxy-l,4-pregnadiene-3,20-dione. Thismixture was refluxed in a nitrogen atmosphere with stirring for a periodof 75 minutes.

The reaction mixture was cooled for a period of about 1 hour to roomtemperature. To this mixture was added g. of ice water and theacetonitrile was removed in vacuo at a temperature below C. The pH ofthe aqueous suspension was adjusted to 6.2 to 6.5 by the addition of asaturated aqueous solution of sodium carbonate. The solid precipitatewhich formed was recovered by filtration. The precipitate was washedwith water and the filtrate and washwaters combined and freeze-dried toseparate a solid material from the water. The solid material wastriturated with methanol and the methanol-insoluble material wasseparated by filtration. The filtrate was concentrated untilcrystallization began. It was then allowed to stand in the refrigeratorovernight and the crystals collected on filter. After several washingswith absolute ether and recrystallization from methanol,16achloroprednisolone-Zl-dihydrogenphosphate was obtained.

Treating a solution of 16u-chloroprednisolone-2l-dihydrogen-phosphate inmethanol with sodium hydroxide (2.5 N) and adjusting the mixture to a pHof 9 to 10 by the addition of sufficient sodium methoxide then addingether to cause precipitation, results in the production of16a-chloroprednisolone-Zl-phosphate disodiurn salts.

In the same manner as given in Example 23 treating 6ozfluoro 21 iodo-l13,17a-dihydroxy-1,4-pregnadiene-3,20- dione with silverdihydrogenphosphate results in the corresponding 21-dihdyrogenpl1osphateof fioc-fluOrO-lfioachloro-1 1p ,17a,2l-trihydroxy-l,4-pregnadiene-3,ZO-dione.

In the same manner given in Example 23,

6u-methy1-16a-chlor'o-1 1/3,17a,21-trihydroxy-1,4-pregnadiene3,20-dione2l-dihydrogenphosphate,

6u-methyl-9a-fluoro4 6a-chloro-1 1;8,17a-dihydroxy-1,4-

pregnadiene 3,20 dione 2'1 -dihydrogen phosphate, 9a-fll10f0- 16tx-Chl01O-I 1 B,17u,21-trihydroxy-1,4-pregnadiene-3,20-dioneZI-dihydrogen phosphate and the respectivedisodium salts thereof can beproduced. EXAMPLE 24 16a-Chl0r0-21-Flu0r0-115,1 7a-Dihydr0Xy-J ,4-Pregnadiene-3,20-Dione A solution of 1 g. of16a-chloro-11,8,17a-dihydroxy-21- iodo-l,4-pregnadiene-3,20-dione in 200ml. of acetonitrile at C. was protected from light and 0.8 ml. ofaqueous solution of silver fluoride was added with stirring. The cloudy,brown-colored solution was stirred continuously at a temperature between45 and 50 and 1.5 ml. of silver fluoride solution added. One hour later,another 1.5 ml. of silver fluoride solution was added. After the lastaddition, stirring was continued for a period of two hours. The brownsuspension was filtered through a bed of diatomaceous earth (Celite) andthe filtrate evaporated at reduced pressure at a temperature of about 50C. The brownish residue was extracted with four 30-ml. portions ofmethylene chloride. The methylene chloride extracts were combined,concentrated to dryness and the residue recrystallized four times frommethanol and Skellysolve B hexanes to give pure 16a-chloro-2-1-fluoro- 11B,17a-dihydroxy-1,4-pregnadiene-3,20-dione.

In the same manner given in Example 24 other 21- fluorides can besynthesized from'the corresponding 160cchloro21-iodo-1l6,l7a-dihydi'oxy-1,4-pregnadiene-3,20- dione and can berecovered by extraction, filtration, recrystallization or chromatographyin conventional manners. By using the starting materials given inExample 21 the following representative 21-fluoro-compounds areobtained:

6a-methyl-1 6a-chloro-21-fluoro-1 1,6,17a-dihydroxy-1 ,4-

preghadiene-3,20-dione;

6a,9oc,2 1-trifluoro-16ot-chloro-1 113,21-dil1ydroxy-1,4-pregnadiene-3,ZO-dionc,

60:,2 l-difluoro-16a-chloro-1 1,8,21-dihydroxy-1-,4-pregnadiene-3,20-dione and EXAMPLE 25 1 da-Chloro-l 15,]7ot-Dihydroxy-1,4-Prgnadiene-3,20 Dione-1 7 -A cetate A solution of 2.0g. of 16a-chloro-115,17u-dihydroxy- 1,4-pregnadiene-3,ZO-dione, 5 ml. ofdistilled acetic anhydride, 500 mg. of p-toluenesulfonic acid and 50 ml.of acetic acid was stirred at room temperature (about 25 C.) under astream of nitrogen for 6 hours. The mixture was then poured withvigorous stirring into 500 ml. of water. The aqueous reaction mixturewas extracted with two 250-ml. portions of chloroform, the extracts werecombined, washed twice with water, then 200 ml. of 5% sodium hydroxidesolution, again twice with water, dried over anhydrous sodium sulfateand evaporated to dryness. The dry residue was redissolved in acetone,poured onto a column of g. alumina and chromatographed with 75 m1. ofSkellysolve B hexanes containing increasing amounts of acetone. Thefractions containing 16a-chl0ro-11e,17a-dihydroxy-1,4-pregnadiene-3,20-dione 17-ac'etate as determinedby papergram were combined, evaporated, and three times recrystallizedfrom ethyl acetate to give crystalline 16a-chloro-115,17a-dihydroxy-1,4-pregnadiene- 3,2 0-dione 17-acetate.

Substituting other lower-hydrocarbon carboxylic acid anhydrides for theacetic anhydride is productive of other 16a chloro11,8,l7a-dihydroxy-1,4-pregnadiene-3,20-dione 17-acylates wherein theacyl radical of the acylate group is the acyl radical of, for example, alower-aliphatic acid, e.g., formic (formic acid plus acetic anhydride),propionic, butyric, isobutyric, Valerie, isovaleric, trimethylacetic,Z-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, heptanoic,octanoic, a-ethyl-isovaleric, a cyclic acid, e.g.,cyclopropylideneacetic, a cycloaliphatic acid, e.g., cyclopentylformic,cyclopentylacetic, fi-cyclopentylpropionic, cyclohexylformic,cyclohexylacetic, fl-cyclohexylpropionic, an aryl or alk-aryl acid,e.g., benzoic,methylbenzoic, 3-methyl-a-naphthoic, an aralkyl acid,e.g., phenylacetic, phenylpropionic, diphenylacetic, triphenylacetic,and the like.

In the same manner given in Example 25, other esters of substituted16a-chloro-11B,17a-dihydroxy-1,4-pregnadiene-3,20-diones can be madesuch as the acetate, .propionate, hexanoate, benzoate, phenylacetate,laurate, and the like of 60t-fiUOlO-160t-ChlOI'O-1118,l7a-dihydroxy-1,4-pregnadiene- 3,20-dione,

60,9oc-difiu0l'0- 1 6ix-chioro-1 lp, 17a-dihydroxy-1,4-pregnadiene-3,20-dione,

6a-methyl-1 6a-fl1ioro-1 1 B, 17 a-dihYdl'OXY- 1 ,4-pregnadiene- 3,ZO-dione,

6a-methyl-9a-fluoro-l 6a-chloro 11j3,1'7a=dihydroxy-1,4-

pregnadiene-3,20-dione and 9a-fluoro-1 6oc-ClilO1O-11,6,17a-dihydroxy-1,4-pregnadiene- 3 ,20-dione.

EXAMPLE 26 16a. Ckloro 11/1,]7a,2] -Trihydrovty-1;4-Pregnadiene-3,

ZO-Dione ZI-Hemfsuccin'ate Sodium Salt [16u-Clil0r0- preduisoloneZJ-Hemisuccinate Sodium Salt] Sodium hydroxide solution (0.1 normal) wasslowly added to a stirred solution of 2 g. of '16a-chloro-l 15,1704, 21trihydroxy 1,4-pregnadiene-3,20-dione 21-hemisuccimate in 50 ml. ofacetone until the pH rose to 7.4. During the addition of NaOH solution,ml. of 'Water was also added.

The solution was concentrated at 25 C. under-vacuum to remove theacetone. The resulting aqueous solution of 16a chloro l18,17u,21-trihydroxy-1,4-pregnadiene-3, 20-dione 2l-hemisuccinate sodiumsalt was filtered, freezedried and recrystallized to give purel6a-chloro-1 15,170, 21-trihydroxy-1,4 pregnadiene-3,20-dione21-hemisuccina-te sodium salt.

In the same manner given in Example 26 other sodium salts of substitutedl6ec-chloroprednisolone 2l-hernisuccinates can be prepared such as:

9a-fiuoro-l 6u-chloro-1 18,17ot,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-hemisuccinate sodiumsalt,

6ot-methyl-l6a-chloro-11B,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dine21-hemisuccinate sodium salt,

6 a-methyl-9 oc-flIlOIO-l 6a-Ch101'O-1 l 5,17 11,2 1 -trihydroxy-1,4-pregnadiene-3,20-dione 21-hemisuccinate sodium salt,

6a-fluoro-l 6oc-Chl0I'0-ll6,17a,21-trihydroxy-l,4-pregnadiene-3,20-dione 21-hemisuccinate sodiumsalt,

6a,9oc-diflu01'0-1 6oc-Ch1OIO-1 15, 17:1,2 l-trihydroxyl,4-pregnadiene-3,20-dione 21-hemisuccinate sodium salt and the like.

We claim:

1. 9oz fluoro l6a-ch1oro-11,9,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione.

2. 9oz fluoro l6a-chloro-llfi,17a,21-trihydroxy-1,4-pregnadiene-3,20-di0ne 21-acylates in which the acyl radical is that ofa hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms,inclusive.

3. 9oz fluoro 16a-chloro-l1,8,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione ZI-acetate.

4. 6u,9a difluoro 16a-chloro-11p,17a,21-trihydroxy-1,4pregnadiene-3,20-dione.

5. 604,901 difluoro-16a chloro-l1B,l7u,21-trihydroxy-1,4-pregnadiene-3,20-dione 2l-acylates in which the acyl radical is thatof a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms,inclusive.

6. 601,91 difluoro 1'6a-chloro-11B,l7a,21-trihydroxy-1,4-pregnadiene-3,20 di0ne 21-acetate.

7. 6a methyl 9afluoro-16a-chloro-11B,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione.

8. 6a methyl 9afluoro-l6a-chloro-11B,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione2l-acylates in which the acyl radical is that of a hydrocarboncarboxylic acid containing from 1 to 12 carbon atoms, inclusive.

9. 6a methyl 9aflu0ro-l6a-ch1oro-llB,17u,2l-trihydroxy-1,4-pregnadiene-3,20-dioneZI-hemisuccinate.

References Cited in the file of this patent UNITED STATES PATENTS2,781,366 Schneider Feb. 12, 1957 2,841,600 Hogg et a1. July 1, 19582,897,218 Sebek et al July 28, 1959 2,980,670 Berg et al. Apr. 18, 19613,016,392 Magerlein et al. Jan. 9, 1962 OTHER REFERENCES Spero et al.:J.A.C.S. (1957) vol. 79, pages 1515-16.

5. 6X, 9A - DIFUORO-16A - CHLORO-11B,17A,21-TRIHYDROXY1,4-PREGNADIENCE-3,20-DIONE 21-ACYLATES IN WHICHTHE ACYL RADICAL IS THAT OF A HYDROCARBON CARBOXYLIC ACID CONTAININGFROM 1 TO 12 CARBON ATOMS, INCLUSIVE.